Accelerating a treatment for ALS

December 19, 2018

Clinical trial success based on stem cell models in the lab

motor neuron
Microscope image of a motor neuron, the type of cell impacted in ALS.


  • A clinical trial, supported in part by the Harvard Stem Cell Institute (HSCI), has shown that the drug retigabine improves a characteristic of motor neurons that is impacted in amyotrophic lateral sclerosis (ALS).
  • The trial originated from early HSCI research that used patient stem cells to make motor neurons and screen for potential drugs.

In ALS, a neurodegenerative disease with no known cure, motor neurons are hyperexcitable — they are overactive and burn out. Researchers at Massachusetts General Hospital (MGH) have completed a clinical trial in patients with ALS, showing that the drug retigabine lowers motor neuron excitability.

“This is the first time in a neurological disease where we used patient stem cells in the lab to identify a potential drug, then brought the drug to clinical trial,” said Brian Wainger, M.D., Ph.D., HSCI Principal Faculty member and leader of the trial.

“It’s exciting that retigabine has a potentially positive effect in patients with ALS, although the benefit on the physiological outcomes in the study may or may not translate into a clinical benefit for patients.”

Better models in the lab

The development of retigabine as a potential ALS treatment started a decade ago, when HSCI Principal Faculty member Kevin Eggan, Ph.D. came up with a better way to study ALS in the lab.

ALS is a complex disorder that can be caused by hundreds of different mutations in dozens of genes. This makes studying the disease difficult, both in mice and in humans. Drug responses observed in ALS patients with one mutation may not be observed in ALS patients with another.

“So far, every ALS therapy studied in animal models has not worked in every patient,” said Eggan. “When you have all of these different mutations, cell models can help you search for commonalities, or categorize different patient subtypes.”

In 2008, Eggan’s lab was the first to create patient-specific stem cell lines to study ALS. The researchers collected skin cells from patients with ALS, reprogrammed them into induced pluripotent stem cells, then converted them into the type of motor neurons affected by ALS.

Since then, Eggan has been able to use a model of ALS in a lab dish to study how different mutations impact disease development.

Targeting hyperexcitability

In 2014, Eggan — collaborating with HSCI Principal Faculty member Clifford Woolf, M.B., B.Ch., Ph.D. — discovered a commonality among the different ALS patient cell lines. They found that most of the genetic mutations caused the motor neurons to become hyperexcitable, or overactive.

The next step was to find and test a drug that reduces excitability in motor neurons. The researchers narrowed in on retigabine: a drug developed to treat epilepsy that prevents seizures using just such a mechanism.

This research was spearheaded by two of Eggan’s and Woolf’s then postdoctoral fellows, Wainger and Evangelos Kiskinis, Ph.D. Both of them now run their own labs that study ALS: Wainger at MGH, and Kiskinis at Northwestern University.

From lab dish to clinical trial

Because retigabine had previously been shown to be safe in people, and because the retigabine results in the ALS lab models were so robust, the researchers were able to go directly from testing in a dish to testing in a clinical trial — bypassing the time-intensive animal testing that typically goes into therapy development.

Working with GlaxoSmithKline, the pharmaceutical company producing retigabine at the time, Wainger and his MGH colleague Merit Cudkowicz, M.D. ran the trial to test the drug’s effects on patients with ALS.

The trial results were positive: retigabine successfully lowered motor neuron excitability in patients with ALS.

Moreover, most of the trial participants have agreed to donate their cell lines for further research, adding to the research team’s genetic catalog.

“With the cell lines that we collect from the trial, we’ll be able to categorize ALS patients by physiology and genotype in a way that no one has ever done,” said Eggan.

The team will further use the cell lines to match patient subtypes to clinical results, and start to tease out the links between which groups of mutations respond best to retigabine or future therapies.

Beyond retigabine

To continue investigating retigabine and other drugs that target motor neuron excitability, Eggan and Woolf founded the biotechnology company QurAlis. Kasper Roet, Ph.D., a former postdoctoral fellow of both Eggan and Woolf, is leading the company.

QurAlis is developing precision medicine for ALS, with one of its programs focusing on hyperexcitability. The company is exploring the opportunity to bring retigabine commercially to ALS patients, and researching alternatives to retigabine that might have the same efficacy with fewer side effects.


This clinical trial was supported by The ALS Association, GlaxoSmithKline, HSCI, and the MGH Neurological Clinical Research Institute. Preclinical studies leading up to the trial, performed at Boston Children’s Hospital and Harvard University, were supported by The ALS Association, HSCI, the National Institute of Neurological Disorders and Stroke, the New York Stem Cell Foundation and Target ALS.

Discover more

MGH press release (2018). Ezogabine treatment shown to reduce motor neuron excitability in ALS patients.

FierceBiotech (2018). ALS-focused QurAlis raises $5.5M in seed money, wins Pfizer ticket to LabCentral.

HSCI news (2014). Patient stem cells help identify common problem in ALS.